T-acute lymphoblastic leukemia/lymphoma (T-ALL) is a very aggressive malignancy. Targetable molecules/pathways of T-ALL are limited because of an insufficient understanding of its genetics and biology. The applicant's long-term goal is to advance the knowledge of the molecular processes for the development, proliferation and survival of T-ALL cells, and to translate the identification of molecular targets into better treatment of T-ALL. Inactivation of PTEN, INK4a and ARF tumor suppressor genes is among the most frequent genetic events in T-ALL. We hypothesized that inactivated Pten and Ink4a/Arf tumor suppressors cooperate in the tumorigenesis of T-ALL. Aberrant molecular pathway/genetic changes in T-ALL, including certain microRNAs, play a role in the pathogenesis of T-ALL, and combined targeted therapy with NOTCH1 and PI3K/mTOR inhibitors, and micorRNAs is effective for T-ALL. Our preliminary studies revealed the mouse T-ALL resembled the human counterparts genetically, histologically and immunophenotypically. In Aim 1, we will determine the impact of INK4a or Arf deficiency on the development of Pten null T-ALL. We plan to evaluate 1) T-ALL biology at the organismal and patho-histologic levels and 2) to determine if the differential tumor suppressor mutational spectrum impacts this effect. In Aim 2, we will characterize Pten and/or Ink4a/Arf deficient T-ALL molecularly. In this aim, we will evaluate (1) the status of known critical genes/pathways involved in the pathogenesis of T-ALL deficient for Pten, Pten and Ink4a/Arf, Ink4a/Arf, Pten and Ink4a, Pten and Arf, Ink4a, and Arf, (2) The expressions levels of miR-150 and -155 in the mouse T-ALL, (3) Functional consequences of expressed miR-150 and -155, and (4) the pertinent targets of miR-150 and -155 in the pathogenesis of T-ALL. In Aim 3, we will evaluate the effects of targeted therapies on Pten and/or Ink4a/Arf deficient T-ALL. We will determine (1) the effects of blocking PI3K/mTOR pathways, (2) the effects of GSI, and (3) the combinatorial effects of PI3K/mTOR inhibitor and GSI on our T-ALL models, (4) the combinatorial effects of PI3K/mTOR inhibitor and GSI on human T-ALL, and (5) the effects of restoring miR-155 and -150 expressions on T-ALL. These studies will likely provide insight into critical genes in the pathogenesis of T-ALL, and provide a platform for effective targeted therapies of T-ALL.